Persons that have had asthma are twice as likely to develop anxiety or depression compared to those that have not had asthma, and this co-morbidity can occur as early as adolescence. This is of particular concern in light of rising rates of asthma in the US. Unfortunately, the mechanisms underlying the association between asthma and internalizing disorders are not clear, and thus proper interventions to minimize rates of anxiety and depression in asthma patients cannot be developed, particularly in the growing population of young people with asthma. To elucidate mechanisms underlying the association between asthma and anxiety/depression, we propose to use a periadolescent mouse model to test two possible mechanisms. The mechanisms are based on two specific aspects of allergic asthma: (1) the highly stressful experiences of potentially life-threatening respiratory distress with severely labored breathing, and (2) chronically-elevated inflammatory responses in the airways. Asthmatic adolescents experience these symptoms during a period of rapid neurological development and maturation of neurotransmitter systems involved in emotion regulation. Severe stress and chronic inflammation during periadolescence can have long-term influences on the regulation of stress hormones (glucocorticoids) and can eventually lead to glucocorticoid dysregulation - a well-known correlate of internalizing disorders. Thus, we propose to use a mouse model to experimentally determine the independent influence of periadolescent labored breathing and airway inflammation on adult glucocorticoid regulation, exploratory and hedonic behavior, and serotonin transporter gene expression - three important correlates of human anxiety and depression and mouse models of these disorders. A validated mouse model is an essential first step in conducting longitudinal and experimental studies to determine the independent effects of labored breathing and chronic inflammation on these symptoms and to model the bidirectional interactions of internalizing behavior and asthma. Discerning the relative role of each of these mechanisms on the development of anxiety and depression would provide key information for evaluating future interventions to minimize the risk of internalizing disorders in adolescents with asthma. PUBLIC HEALTH RELEVANCE: Asthma is the most common chronic condition for children and adolescents in the U.S., with a current prevalence of 9 percent, or approximately 5 million youth. Public health concerns are compounded by the fact that asthma is often co-morbid with anxiety and depression - asthma patients suffer from anxiety and depression at twice the rate as persons without asthma. The physiological processes underlying this co-morbidity are not clear, and thus appropriate intervention methods to minimize rates of these internalizing disorders in asthmatic adolescents are necessarily limited. Our proposed research will use a periadolescent mouse model to compare the influence of two asthma symptoms (labored breathing, airway inflammation) on the development of anxiety- and depression-related behavior and neuroendocrine processes. The relative role of each of these two symptoms in the development of internalizing disorders is key to developing future interventions to minimize anxiety and depression in patients with asthma.